tbuckley/cabot-search huggingface dataset:
Major Revisions in Pancrustacean Phylogeny and Evidence of Sensitivity to Taxon Sampling
Authors: James P Bernot, Christopher L Owen, Joanna M Wolfe, Kenneth Meland, Jørgen Olesen, Keith A Crandall
Journal: Molecular Biology and Evolution (2023)

Abstract The clade Pancrustacea, comprising crustaceans and hexapods, is the most diverse group of animals on earth, containing over 80% of animal species and half of animal biomass. It has been the subject of several recent phylogenomic analyses, yet relationships within Pancrustacea show a notable lack of stability. Here, the phylogeny is estimated with expanded taxon sampling, particularly of malacostracans. We show small changes in taxon sampling have large impacts on phylogenetic estimation. By analyzing identical orthologs between two slightly different taxon sets, we show that the differences in the resulting topologies are due primarily to the effects of taxon sampling on the phylogenetic reconstruction method. We compare trees resulting from our phylogenomic analyses with those from the literature to explore the large tree space of pancrustacean phylogenetic hypotheses and find that statistical topology tests reject the previously published trees in favor of the maximum likelihood trees produced here. Our results reject several clades including Caridoida, Eucarida, Multicrustacea, Vericrustacea, and Syncarida. Notably, we find Copepoda nested within Allotriocarida with high support and recover a novel relationship between decapods, euphausiids, and syncarids that we refer to as the Syneucarida. With denser taxon sampling, we find Stomatopoda sister to this latter clade, which we collectively name Stomatocarida, dividing Malacostraca into three clades: Leptostraca, Peracarida, and Stomatocarida. A new Bayesian divergence time estimation is conducted using 13 vetted fossils. We review our results in the context of other pancrustacean phylogenetic hypotheses and highlight 15 key taxa to sample in future studies.
IFN-γ–dependent interactions between tissue-intrinsic γδ T cells and tissue-infiltrating CD8 T cells limit allergic contact dermatitis
Authors: Miguel Muñoz-Ruiz, Miriam Llorian, Rocco D'Antuono, Anna Pavlova, Anna Maria Mavrigiannaki, Duncan McKenzie, Bethania García-Cassani, Maria Luisa Iannitto, Yin Wu, Robin Dart, Daniel Davies, Mariam Jamal-Hanjani, Anett Jandke, Dmitry S. Ushakov, Adrian C. Hayday
Journal: Journal of Allergy and Clinical Immunology (2023)

Elicitation of allergic contact dermatitis (ACD), an inflammatory type 4 hypersensitivity disease, induces skin infiltration by polyclonal effector CD8 αβ T cells and precursors of tissue-resident memory T (T
Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors
Authors: Letian Song, Shenghua Gao, Bing Ye, Mianling Yang, Yusen Cheng, Dongwei Kang, Fan Yi, Jin-Peng Sun, Luis Menéndez-Arias, Johan Neyts, Xinyong Liu, Peng Zhan
Journal: Acta Pharmaceutica Sinica B (2023)

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed.
The impact of social restrictions on the incidence and microbiology of peritonsillar abscess: a retrospective cohort study
Authors: Tejs Ehlers Klug, Thomas Greve, Lisa Caulley, Sara Hillerup
Journal: Clinical Microbiology and Infection (2023)

We aimed to explore the impact of social distancing on the incidence and microbiology of peritonsillar abscess (PTA).
Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy
Authors: Xiaoshuang Niu, Menghan Wu, Guodong Li, Xiuman Zhou, Wenpeng Cao, Wenjie Zhai, Aijun Wu, Xiaowen Zhou, Shengzhe Jin, Guanyu Chen, Yanying Li, Jiangfeng Du, Yahong Wu, Lu Qiu, Wenshan Zhao, Yanfeng Gao
Journal: Acta Pharmaceutica Sinica B (2023)

Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients. Here, we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells, especially myeloid derived suppressor cells (MDSCs) and CD8
PB2181: CLINICAL FEATURES, TREATMENT APPROACHES, AND OUTCOMES IN ROSAI-DORFMAN DISEASE: A RETROSPECTIVE ANALYSIS OF 104 PATIENTS
Authors: Long Chang, Bing Qiao, He Lin, Minghui Duan, Jian LI, Dao-Bin Zhou, Chun-Yan Sun, Xin-Xin Cao
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Rosai-Dorfman disease (RDD) is a rare benign histiocytosis disorder of unknown cause. It often manifests as massive cervical lymphadenopathy in children and young adults The etiology, clinical spectrum, genomic analyses and outcomes are not well defined due to the rarity and challenging histopathology. No standard therapy has been established on the results of prospective clinical studies. Aims: We retrospectively studied the clinical features, laboratory tests, genomic analyses, treatment approaches, and outcomes of RDD patients in two centers. Methods: Patients with RDD, diagnosed between January 2005 and December 2022 at Peking Union Medical College Hospital (Beijing, China) and Tongji Medical College Union Hospital (Wuhan, China) were included in this retrospective study. Event-free survival (EFS) was defined as the duration from diagnosis to the first event, including the progression of disease or death. Results: We included 104 RRD patients in the study. Of these patients, 59 (55.6%) were male, with a median age at diagnosis of 44 (range, 3-86) years. The median duration from symptoms onset to diagnosis was 8 months (range 1-123). 8 (7.7%) patients had classical (nodal only) and 96 (92.3%) had extra-nodal RDD (40 unifocal, 8 single-system multifocal and 46 multisystem). The most common presenting symptom was subcutaneous masses (29%), followed by nasal congestion (16%) and palpable lymphadenopathy (13%). The most common organ involved was subcutaneous tissue (33%), followed by bone (26%) and lymph node (25%). Central nervous system involvement was seen in 17 patients (16.3%). Among the 46 patients who underwent molecular study, a total number of 97 mutations were present in 33 patients, of which MAP2K1 (22.2%) was the most common alteration, followed by KRAS (17.8%) and BRAF (11.1%). The first-line treatment was commonly surgical excisions (44%), immunomodulating agents (20%) and prednisone (13%). After a median follow-up of 44 months (range 2-220), 4 (3.4%) patients died of progression disease and 31 (23.7%) patients relapsed. The estimated 4-year OS was 96.5%. The estimated median EFS was 95 months. To evaluate the prognostic factors of EFS using univariate analysis, extranodal patients with 3 or more organs involved and lung involvement at baseline had significantly shorter EFS. EFS were also evaluated using multivariate Cox regression model, and extranodal patients with 3 or more organs remained predictive of poorer EFS (HR 2.428, 95% CI 1.088–5.417). Summary/Conclusion: RDD is a heterogeneous histiocytosis disease with various extranodal presentations. Patients with 3 or more organs involved at baseline predicted poor outcomes.Keywords: Langerhans Cell Histiocytosis
PB2031: NEXT GENERATION SEQUENCING IN MYELOID NEOPLASMS: DEVELOPING WORLD DATA FROM SINGLE CENTRE
Authors: Nida Anwar, Naveena Fatima, Aisha Arshad, Tahir Shamsi
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: Studies utilizing NGS have identified a core set of recurrently mutated myeloid genes in majority of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) that not only characterize disease but also impact therapeutic decision making. Aims: In this study, we performed NGS in myeloid malignancies and reported our institutional findings. Methods: A total of 36 myeloid neoplasms patients diagnosed by bone marrow biopsy were included. Informed consent was taken from all the patients. Bone Marrow cytogenetics was performed on all the samples. The NGS analysis for a panel of 54 genes including tumor suppressor and oncogenic hotspots associated with myeloid malignancies was performed using DNA samples. Results: The median (IQR) age of participants was 41 (15-81) years, 27 (75%) patients were MDS followed by AML 8(22%) and CMML 1(3%). Median hemoglobin (g/dl), platelet count (x109/L), total leucocyte count (x109/L) and absolute neutrophil count was 9.5(4-16), 90 (12-477), 3.5 (1-115) and 1.6 (0.1-46) respectively. Normal karyotype was observed in 22(61%) of patients and mutations were detected in 17 (47%). Out of 17 patients, 3 (8%) had mutations on more than one gene including RunX1, CDKN2A, GATA2, ASLX1, BCORL1, TET2, EZH2. Three (8%) patients had mutations on NRAS, ASXL1, RUNX1. TET 2 and TP53 found in each of the 2(6%) patients. However, CEBPA, CDKN2A and DNMT3A were found in each of three patients. Patients who had normal karyotype was found to have mutations on TP53, ASXL1, CEBPA, RUNX1, CDKN2A, DNMT3A and NRAS. In MDS, mutations were found in 13(48%) patients including mutations on TP53, RUNX1, CDKN2A, TET2, ASLX1, NRAS while TP53, RUNX1, CDKN2A, NRAS and ASXL1 were found in patients with normal karyotype. In AML, mutations were found in 3(38%) including mutations on TET2, CEBPA and DNMT3A with normal karyotype. A single CMML case had normal karyotype with ASXL1 mutation. Summary/Conclusion: Integration of NGS has refined prognosis and clinical management of patients. Nevertheless, some patients with normal karyotype in our study was found to have poor prognosis mutations. TET2 mutation was helpful for the decision of treatment with HMA even in the older patients. Genetic counseling and screening of the family members was also taken into consideration on the basis of mutations like GATA 2. Being a part of resourced limited country, utilization of NGS is difficult yet helpful for providing better risk stratified treatment plans for patients as compared to conventional risk based prognostic assessment. Keywords: MDS/AML, Acute myeloid leukemia, ADAMTS13, MDS
PB2036: PERIPHERAL BLOOD CYTOPENIA, AN EARLY INDICATOR OF INBORN ERRORS OF IMMUNITY
Authors: Zivanai Cuthbert Chapanduka, Helena Cornelissen, Ernest Musekwa, Richard Glashoff, Monika Esser, Moleen Zunza, Deepthi Abraham
Journal: HemaSphere (2023)

Topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research Background: Inborn Errors of Immunity (IEI) are inherited monogenic disorders resulting in defective immune response. Non-infectious presentations are increasingly more apparent. Widely available, cost-effective early indicators are needed. Peripheral blood cytopenia may be a presenting laboratory feature or observed secondary phenomenon. Aims: This retrospective review of the South African Primary Immunodeficiency Registry (SAPIDR) aimed to assess the haematological indices at presentation; their association with International Union of Immunological Societies (IUIS) 2019 classification and mortality. Methods: Haematological indices of patients on the SAPIDR were retrospectively reviewed. Presentation with cytopenia and the associated with molecular diagnosis and outcome was analysed. Results: Of 396 patients on the SAPIDR, 66% (n=257) had available haematological results. Sixty percent were males and 85% under 18 years. The median age at diagnosis was 76 months (range from birth to 420 months). None were from a consanguineous relationship and 27% had a known family history of IEI. Majority (53%) had predominantly antibody deficiency. At presentation, infection was prominent (86%) followed by cytopenia (62%). Neutropenia was associated with IUIS III [Odds Ratio (OR) 3.65 Confidence interval (CI) (1.44-9.25)], thrombocytopenia with IUIS II [OR 14.39 CI (2.89-71.57)], lymphopenia with IUIS I [OR 12.16 CI(2.75-53.73)] and pancytopenia with IUSI I [OR 12.24 CI (3.82-39.05)] and IUIS II [OR 5.99 CI (2.80-12.76)]. Molecular diagnosis was confirmed in 30% where cytopenia at presentation [OR 2.26 (1.42-3.59)] namely persistent cytopenia [OR1.86 (1.06-3.26)] were predictive. Cytopenia showed shorter overall survival [OR 2.81 CI (1.288-4.16)]. Summary/Conclusion: Cytopenia(s) that are severe, persistent, unusual and/or recurrent should prompt further investigation for IEI. The full blood count and leucocyte differential, may facilitate earlier identification and serve as an adjunct to definitive molecular classification. Keywords: Immunodeficiency, Immunity, Pancytopenia
PB2277: PROGNOSTIC SIGNIFICANCE OF SERUM MONOCLONAL PROTEINS BASED ON IMMUNOFIXATION ELECTROPHORESIS IN B CELL NON-HODGKIN LYMPHOMA
Authors: Yuyang Gao, Xiaoyan Feng, Wenting Song, Zhaoming LI, Mingzhi Zhang
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: The presence of serum monoclonal component has been associated with poor outcomes in various hematological malignancies. Aims: The current study focused on exploring the prognostic role of serum monoclonal component in B-cell non-Hodgkin lymphoma. Methods: The clinical indicators and follow-up data of 314 patients with information on serum immunofixation electrophoresis (IFE) at diagnosis were available with B-cell non-Hodgkin lymphoma in our hospital from May 2013 to November 2021 were retrospectively analyzed. Cox proportional hazard model was used for univariate and multivariate analyses. Kaplan–Meier curves were used to calculate survival rates and draw survival curves. The log-rank test was applied to compare differences between groups. Results: IFE was positive in 61 patients (19%). Baseline features were comparable between pairs of groups, poor ECOG PS, B symptoms, advanced stage and high-risk IPI score were significantly more frequent in the +IFE group. Shorter PFS and OS of B-NHL patients were observed in patients who presented at diagnosis with the +IFE was the independent predictor of PFS (HR = 3.773, 95% CI 1.292-11.023, P =0.015 in indolent lymphomas; HR = 2.598, 95% CI 1.239-5.451, P =0.012 in aggressive lymphomas) and OS (HR =14.693, 95% CI 3.660-58.985, P <0.001 in aggressive lymphomas) in multivariate analysis. Moreover, integrating IFE into the IPI-M1, IPI-M2 and IPI-M3 models improved the area under the curve (AUC) for more accurate survival prediction and prognosis. Summary/Conclusion: Serum monoclonal proteins is a significant prognostic indicator for newly diagnosed B-cell non-Hodgkin lymphoma that can early identify patients with poor prognosis and guide clinical treatment decisions. Keywords: Non-Hodgkin’s lymphoma, B cell lymphoma
PB1999: TOBACCO SMOKING IN MDS PATIENTS – ANALYSIS FROM THE MDS PALG REGISTRY
Authors: Rafal Machowicz, Karol Lis, Jagoda Rytel, Anna Jachalska, Pawel Szwedyk, Oktawia Sosnia, Elzbieta Wiater, Agata Obara, Dorota Krochmalczyk, Anna Kopinska, Malgorzata Gajewska, Anna Masternak, Agnieszka Kopacz, Magdalena Olszewska-Szopa, Aleksandra Golos, Edyta Subocz, Joanna Drozd-Sokolowska, Grzegorz Basak, Krzysztof Mądry
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: Tobacco smoking is an independent risk factor for developing MDS (myelodysplastic syndrome). Azacitidine is a widely used hypomethylating treatment for higher-risk MDS patients. Interestingly, so far this treatment was not analyzed in the context of smoking in a large group of patients. Aims: The aim of this study was the analysis of tobacco smoking and azacitidine treatment based on the data from the PALG (Polish Acute Leukemia Group) MDS Registry Methods: Retrospective analysis of 2851 MDS patients reported in the Registry in the years 2009-2022 was performed. Further analyses included 2290 patients with smoking data available. Results: In the analyzed group 741 patients (32%) declared as smokers and 1549 (68%) as non-smokers. Azacitidine was used in 707 patients, with a higher proportion among smokers 31% vs. 25% in non-smokers (p< 0.0001). Among smokers, 74% were male, which was much higher than 47% in non-smoking patients (p < 0.0001), this proportion in patients treated with azacitidine was 60% (p=NS). Smokers were diagnosed with MDS at a younger age: 68 vs. 71 for non-smokers (p = 0.0001), this effect was also present in MDS patients treated with azacitidine: 66 vs. 70 years at diagnosis (p = 0.001). A suspected higher concentration of erythropoietin was not found. Among complete blood count parameters, only a slightly lower platelet count (median 93 vs 97,5 G/l; p=0.027) was observed in smokers. Smokers had generally a worse prognosis (Fig 1) – 24-month median survival vs. 28 months in non-smokers (p log-rank 0.017). This effect is even more pronounced in a group of 205 heavy smokers (over 20 cigarettes per day and over 10 years of smoking) with 19-month survival (p = 0.003.) Regression analysis further confirmed that this negative effect of smoking is dose-dependent. Survival analysis of smokers and non-smokers treated with azacitidine did not reveal a significant difference (19 vs. 21 months; p=NS), but in heavy smokers, a detrimental effect was visible at 11 vs. 21 months (p = 0.0001). Summary/Conclusion: This first analysis of smoking and azacitidine treatment confirms the general pattern associated with tobacco smoking in Polish MDS patients, but also highlights new aspects (e.g. higher demand for azacitidine treatment, younger age of diagnosis in smokers) and opens this field for further analyses.Keywords: Hypomethylating agents, Azacitidine, MDS
PB1822: INHIBITION OF THE DNA DAMAGE RESPONSE: A POSSIBLE NEW ROUTE IN ACUTE MYELOBLASTIC LEUKEMIA TREATMENT
Authors: Beatriz Lapa, Maria Inês Costa, Joana Jorge, Raquel Alves, Ana Bela Sarmento-Ribeiro, Ana Cristina Gonçalves
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: DNA integrity is threatened by endogenous and exogenous factors that can induce DNA damage. Therefore, cells have developed mechanisms to protect the integrity of the genome and repair damaged DNA, called the DNA damage response (DDR). The DDR includes sensor proteins (e.g. PARP1/2), signaling mediators and transducers, and effector molecules (e.g. CHK1/2). Increased DNA damage and altered DDR mechanisms are critical features of genetic instability that are potentially implicated in the pathogenesis of acute myeloblastic leukemia (AML). AML is a clonal stem cell and hematopoietic progenitor cell disease characterized by an arrest in myeloid differentiation and increased proliferation. Aims: The aim of the study was to evaluate the therapeutic potential of DDR inhibition in AML using in vitro models. Methods: To this end, AML cell lines (HEL, HL-60, K-562, KG-1, LAMA-84 and NB-4) were incubated in the absence or presence of increasing concentrations of two DDR inhibitors, CCT245737 (CHK1 inhibitor) and niraparib (PARP1/2 inhibitor). Cell density and viability were assessed by trypan blue assay during 72h. Cell cycle was assessed by flow cytometry using propidium iodide/RNAse labeling. Cell death was determined by flow cytometry using annexin V/7-AAD staining and by light microscopy (May-Grünwald-Giemsa staining). The results were analyzed statistically, considering a significance level of 95%. Results: CCT245737 and niraparib reduced cell proliferation and viability in a dose-, time- and cell-line-dependent manner. KG-1 cells (IC50 of 47 μM at 48 hours) were the most sensitive to CHK1 inhibition while LAMA-84 cells (IC50 of 78 μM at 48 hours) were the most resistant. The most sensitive cell line to niraparib was NB-4 (IC50 of 20 μM at 48 hours) and the most resistant was KG-1 (IC50 of 68 μM at 48 hours). Both inhibitors led to an increase in the percentage of cells in late apoptosis, confirmed by morphological evaluation. A cytostatic effect by blocking the cell cycle in G0/G1 phase was also detected. Summary/Conclusion In conclusion, AML cell lines have different sensitivities to CCT245737 and niraparib. KG-1 and NB-4 cells appear to be the most sensitive while LAMA-84 and KG-1 cells appear to be the most resistant to CHK1 and PARP1/2 inhibition, respectively. Thus, this work may help to identify new therapeutic approaches that can improve the treatment of AML patients. Keywords: Targeted therapy, Apoptosis, DNA repair, Acute myeloid leukemia
PB2250: THE IMPACT OF JAK2V617F MUTATION POSITIVITY IN ESSENTIAL THROMBOCYTHEMIA:ABOUT 74 CASES.
Authors: Arij Cheffai, Slama Nader, Ouahchi Ines, Wiem Boufrikha, Laabidi Baraa, Sarra Boukhriss, Adnene Laatiri
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: The era of molecular diagnosis of essential thrombocythemia (ET) began in 2005 with the discovery of the JAK2V617F mutation. JAK2V617F represents the most frequent driver mutation in ET. It is positive in 50-60% of cases. Interestingly, the mutational status defines different subtypes of ET with different clinical, biological and evolutionary characteristics. Aims: The aim of our study was to compare the characteristics of our patients according to JAK2V617F mutational status in ET. Methods: A retrospective study was conducted at the Clinical Hematology Department of Fattouma Bourguiba Hospital in Monastir on 74 patients followed up for ET between April 2008 and April 2022. The search for JAK2V617F mutation was performed by the allelic discrimination technique using Taqman technology. Results: The molecular study revealed a positive JAK2V617F mutation in 58.1% of cases. The mean age of JAK2V617F mutation-positive patients was 62.1± 13.8 years, with extremes of 31 and 83 years. No gender predominance was observed in these patients (sex ratio: 0.95). In our series, the presence of the JAK2V617F mutation was associated with a significantly higher hemoglobin level compared to patients without the mutation (p=0.04). A lower incidence of bleeding complications was also found in this group (p=0.02). However, there were no significant differences between the two groups for age at diagnosis, gender, frequency of splenomegaly, and platelet and white blood cell counts (WBC) at diagnosis. Similarly, no significant difference was observed for thrombotic complications, leukemic transformation and progression to myelofibrosis. The table below summarizes the different parameters compared between the JAK2V617F positive and negative groups. Table: Comparative table of characteristics according to JAK2V617F mutational statusSummary/Conclusion: The clinico-biological and evolutionary differences reported in the literature between the JAK2V617F positive and negative groups were more marked than those found in our study. This is most likely due to our relatively small sample size. Keywords: Thrombocythemia, Hemorrhage, Thromboembolic events